Certain benzimidazolium compounds substituted in the 1, 2, 3-positions



llniteci states 2,965,647 Patented Dec. 20, 1960 Free CERTAINTEENZKNHDAZCLIUM COMPOUNDS SUB- THTUTED IN TEE 1,2,3-PS1TIONS ChristianWiegand and Wolfgang Wirth, both Farbenfabriken Bayer, A.G.,Wuppertal-Elberfeld, Germany This invention relates to novel chemicalcompounds useful in chemotherapy and more particularly it is concernedwith certain novel benzimidazoles that are useful in altering bloodpressure.

It is known that certain compounds such as epinephrine and thesympathomimetic amines are effective agents for increasing bloodpressure. However, they have the disadvantage of being highly toxicmaterials and also or" being substances toward which many personsexhibit idiosyncratic reactions. Furthermore, the use of these agents incases of chronic hypotension has been found to result in the developmentof a tolerance and thus a need has been felt for other agents that mightbe employed in treatment of hypotension which might have the advantagesof reduced toxicity, prolonged action, strong vasoconstrictor effectsand reduced incidence of idiosyncratic reactions.

Various agents for reducing blood pressure have long been known, notablynitroglycerin, nicotinic alcohol derivatives, reserpine, priscoline andganglionic blocking agents. Nitroglycerin has the disadvantage ofrapidly producing an effect which is not sustained; the nicotinicalcohol derivatives and reserpine are disadvantageous for a variety ofreasons, and the ganglionic blocking agents are much too dangerous foruse except under carefully supervised conditions, such as in a hospital.

It is known that certain derivatives of imidazole, when administered,produce marked efiects on the blood pressure. Thus,2-benzyl-3,4-dihydroirnidazole produces strong vasodilator effects,whereas, in contrast, 2-(anaphthylmethyl)-3,4-dihydroimidazole is apotent vasoconstrictor. It has been considered in the prior art thatreplacement of the alkyl or aralkyl groups in the 2-position by an arylor heterocyclic radical would lead to compounds having practically noeffect on the blood pressure.

The surprising discovery is now made that compounds which raise theblood pressure considerably and for prolonged periods can be obtained byproducing benzimidazolium compounds of the following general formula:

In the above formula, R represents an unsaturated short-chain aliphaticradical, for example allyl, methallyl, haloallyl, or crotyl, while R andR stand for identical or different aryl, aralkyl, heteroaryl, andheteroaralkyl radicals, which may be substituted in turn. X is anontoxic anion. It will be understood that the benzene nucleus of thebenzimidazole moiety may be substituted by one or more monovalentsubstituents such as halogen, alkyl, alkoxy, acylsulfono, sulfonoamido,nitro, or amino groups.

Even in small doses these compounds show a pronounced and sustainedelevating effect on the blood pressure. A pressure increase lastingseveral hours, for instance, is produced in the narcotized cat byadministration of only one to two milligrams of a representativecompound of the group.

Various methods for preparing the benzimidazolium compounds according tothis invention are available. Compounds of the type, for example:

may be reacted with reactive esters of unsaturated aliphatic alcohols,for instance, with esters of hydrohalic acids or esters of alkylsulfonicand arylsulfonic acids; or compounds of the type:

may be subjected to the action of reactive esters of hydroxym'ethylarylor hydroxymethyl heteroaryl compounds. As an example of the firstreaction, the known 1-benZyl-2-phenylbenzimidazole may be reacted withallyl bromide and, furthermore, l-allyl-2 phenylben1imidaz'ole may bereacted with benzyl chloride.

Alternatively, compounds of the type may be reacted with arylcarboxylicacids, aralkylcarbofylic acids, heteroarylcarboxylic acids, orheteroaralkylcarboxylic acids, or with reactive acid derivatives thereoffollowed by closure of the benzimidazole ring by conven tional methods.

To facilitate a fuller and more complete understand ing of the subjectmatter of this invention, certain specific examples herewith follow butit is clearly to be understood that these examples are provided by wayof illustra tion merely and are not to be construed as imposinglimitations upon the scope of the invention defined in the subjoinedclaims.

Example I Z-benzyl-benzimidazole is heated in the presence of an aliquotamount of sodium ethoxide with a small excess of crotyl chloride, thesodium chloride formed is removed by vacuum filtration, and the residueis evaporated, then dissolved and reprecipitated from dioxane to give1-crotyl-2-benzyl-benzimidazole, melting at 205208 C. Administration ofthe product causes raising of the blood pressure.

Example II Z-benzyl-benzimidazole is heated with slightly more than 2moles of allyl bromide in the presence of 1 mole of sodium ethoxide,then the mixture is worked-up as described in Example I and the productis reprecipitated from methanol to givel,3-diallyl-2-benzyl-benzimidazolium chloride, melting at 277-278 C.Administration of the product causes raising of the blood pressure.

Example III 1-(fi-methylallyl)-2-benzyl-benzimidazole is prepared from,B-methylallyl chloride and 2-benzyl-benzimidazole by heating thesereactants together with sodium ethoxide in a procedure according toExample I. The hydrochloride of this compound is found to melt at118-120 0, following reprecipitation from acetone. This compound isheated for a short time under reflux with twice the stoichiometrical'lyequivalent amount of allyl bromide and, after boiling for about 1 hour,the liquid solidifies. After grinding with ethyl acetate andredissolution in isopropanol,l-(fl-methylallyl)-2-benzyl-3-allyl-benzimidazolium chloride is obtainedmelting at 265-267 C. with decomposition. Administration of the productcauses raising of the blood pressure.

Example IV 2-(a-hydroxybenzyl)-benzimidazole is heated for several hourswith a small excess of crotyl chloride in the presence of the calculatedamount of sodium ethoxide and the precipitated sodium chloride isfiltered off under suction. 1 crotyl 2 (a hydroxybenzyl) benzimidazolecrystallizes upon cooling and when it has been recrystallized fromabsolute alcohol, it melts at 162- 163 C. Administration of this productcauses lowering of the blood pressure.

Example V Example VI About 1 part by weight of2-phenyl-1-benzyl-benzimidazole (melting point, 136l37 C.) is heated,under reflux, with 2 /2 parts by weight of allyl bromide. Precipitationof l-allyl-2-phenyl-3-benZyl-benzimidazolium bromide begins after ashort time. Following evaporation of excess allyl bromide andredissolution in isopropyl alcohol, colorless crystals, melting atl84-l86 C., are obtained. Upon administration, this product causes arise in blood pressure.

Example VII Approximately equal parts by Weight of 1-allyl-2-(2'-furyl)-benzimidazole (which may be prepared according to Example V) andof 2-thienylmethyl chloride are heated together to about 100 C. forseveral hours. The mass begins to solidify in about 1 hour. Followingrebenzimidazolium chloride.

dissolution in a mixture of isopropyl alcohol and ethyl acetate, fine,colorless crystals of l-allyl-2-(2'-furyl)-3-(2'-thienylmethyl)-benzirnidazolium chloride are obtained Which meltWith decomposition at l9l-193 C. and which are readily soluble in water.Upon administration, this product causes a rise in blood pressure.

Example VIII Example IX Approximately equal parts by weight of4-chlorobenzyl chloride and 1-al1yl-2-phenylbenzimidazole (melting point-96 C.), which may be prepared from Z-phenylbenzimidazole by the methodaccording to Example V, are heated on a Water bath. During 1 hour, theentire mass solidifies in crystalline form. After grinding with ethylacetate and reprecipitation from chloroform by addition of carbontetrachloride, fine, colorless needles of 1 allyl 2 phenyl 3 (4'chlorobenzyl) benzimidazolium chloride, melting at 223-225 C. areobtained, which are very easily water-soluble. Upon ad ministration,this product causes a rise in blood pressure.

Having thus described the subject matter of this invention, what it isdesired to secure by Letters Patent of the United States is:

1. l,3-diallyl-2-benzyl-benzimidazolium bromide.

2. 1 (t3 methylallyl) 2 benzyl 3 allyl benzimidazolium chloride.

3. l-allyl-2-pheny-l-3-benzyl-benzirnidazolium bromide.

4. 1 allyl 2 (2' furyl) 3 (2 thienylmethyD- 5. l allyl 2 phenyl 3 (2thienylmethyl)- benzimidazoliurn chloride.

6. A benzimidazolium compound selected from the group consisting of1,3-diallyl-2-benzyl-benzirnidazolium bromide, 1 (fl methylallyl) 2benzyl 3 allylbenzimidazolium chloride, 1allyl-2-phenyl-3-benzyl-benzimidazolium bromide,l-allyl-2-(2'-furyl)-3-(2'-thienylmethyD-benzirnidazolium chloride and1-allyl-2-phenyl- 3 2'-thienylmethyl -benzimid azolium chloride.

References Cited in the file of this patent UNITED STATES PATENTS2,623,879 Ringwald et a1. Dec. 30, 1952

6. A BENZIMIDAZOLIUM COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1,3-DIALLYL-2-BENZYL-BENZIMIDAZOLIUM BROMIDE, 1 (3-METHYLALLYL) -2 - BENZYL- 3- ALLYLBENZIMIDAZOLIUM CHLORIDE, 1-ALLYL-2-PHENYL-3-BENZYL-BENZIMIDAZOLIUM BROMIDE. 1-ALLYL-2-(2''-FURYL) -3-(2''-THIENYLMETHYL)-BENZIMIDAZOLIUM CHLORIDE AND 1-ALLY-2-PHENYL3-(2''-THIENYLMETHYLY-BENZIMADAZOLIUM CHLORIDE. 